Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3,4,5,3,7,8-octahydroisoquinoline

ABSTRACT

Optically active 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline having the formula (I) is prepared by asymmetric hydrogenation of the corresponding 3,4,5,6,7,8-hexahydro-compound or of the new 1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline dihydrogenated phosphate in the present of chiral iridium-phosphine complexes. This product is an intermediate product in the synthesis of cough-relieving dextromethorphanne and analgesic levorphanol. ##STR1##

This application is a 371 of PCT/EP96/02923, filed on Jul. 3, 1996.

This application is a 371 of PCT/EP96/02923, filed on Jul. 3, 1996.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for the preparation of1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline of the formula##STR2## in optically active form by asymmetric hydrogenation.

It further relates to a novel salt of1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline and a process forits preparation.

It also relates to a novel chiral diphosphine having a ferrocenestructure and to its use for the preparation of catalysts for asymmetrichydrogenation, to the iridium-phosphine complexes obtainable from thediphosphine and also to a novel chiral amino-phosphine having aferrocene structure as intermediate in the synthesis of the diphosphine.

2. Background Art

1-(p-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (I) is anintermediate in the synthesis of the antitussive dextromethorphan andthe analgesic levorphanol. The targeted preparation of the effectiveenantiomer of dextromethorphan requires I in the (S)-(-)-configuration,and the synthesis of levorphanol requires I in the(R)-(+)-configuration. A classical process for obtaining thesestereoisomers is racemate resolution, which, in this case, is alsopossible without the use of optically active ancillary reagents (DE-A 3436 179). The main disadvantage of almost all racemate resolutions isthat at least half of the substance used has to be disposed of as wastein the form of the "undesired" enantiomer unless, exceptionally, it toois required in comparable quantities. In the present case, racemizationis also possible, meaning that the undesired enantiomer can be recycledas racemate and there are in theory no losses (O. Schnider et al., Helv.Chim. Acta 1954, 37, 710; A. Brossi, O. Schnider, Helv. Chim. Acta 1956,39, 1376; HU 170 924). This method is, however, rather involved.

A significantly better strategy is the targeted synthesis through astereoselective reaction, starting from a prochiral precursor. It isknown that N-acyl-1-benzylidene-1,2,3,4,5,6,7,8-octahydroisoquinolinescan be stereoselectively ("asymmetrically") hydrogenated at theexocyclic double bond using chiral ruthenium-phosphine complexes (JP-A05/092 958). This process does, however, have the disadvantage that anN-acylated product is obtained whose acyl group has to be cleaved offagain in a further synthesis step. Furthermore, the benzylidenecompounds are for their part formed as E/Z-isomer mixtures, of which ineach case only the Z-isomer can be used for the stereoselectivehydrogenation.

BROAD DESCRIPTION OF THE INVENTION

The object of the present invention was, therefore, to provide astraightforward process which produces the title compound directly ingood optical purity.

According to the invention, the object is achieved by the process of theinvention.

It has been found that by using optically active iridium-phosphinecomplexes as catalysts,1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline of the formula##STR3## or a salt thereof can be directly hydrogenated asymmetricallyto give the S- or R-enantiomers of the title compound. The nature andconfiguration of the catalyst determine which enantiomer is formed inpreference and how high the optical yield is. The optically activeiridium-phosphine complexes which may be used are, in principle, anychiral complexes of iridium in low oxidation state which havepolydentate chiral phosphines as ligands, are able to coordinate withhydrogen and are catalytically active. For the hydrogenation, it ispossible to use both neutral and cationic iridium-phosphine complexes ascatalysts. These catalysts can also be produced in situ. In this case,the active catalyst is formed directly in the hydrogenation reaction byligand-exchange from a precursor complex of iridium, the correspondingchiral ligand and hydrogen. The precursor complex used can, for example,be a complex of the general formula Ir₂ (L_(c))₂ Cl₂ !, where L_(c) is aC₄₋₁₂ -diene. In this case, a neutral complex is obtained. If, on theother hand, a complex of the general formula Ir(L_(c))₂ !⁺ BF₄ ⁻, whereL_(c) is as defined above, is used, for example, a cationic complex isformed.

Preference is given to using pre-formed cationic complexes of thegeneral formula

     IrL.sub.c L.sub.p !.sup.+ A.sup.-                         III

which, with hydrogen, form the actual catalytically active species. Inthis connection, L_(c) is a C₄₋₁₂ -diene, L_(p) is a chiral bidentatephosphine and A⁻ is an anion. Here, bidentate phosphines are taken tomean not only diphosphines, but also phosphines which contain a secondnon-phosphorus coordinating atom, such as, for example,amino-phosphines. The A⁻ anion is preferably a non-coordinating or onlya weakly coordinating anion, such as, for example, tetrafluoroborate,hexafluorophosphate, hexafluoroantimonate, perchlorate, phosphate,acetate, trifluoroacetate, trifluoromethanesulfonate ortoluene-4-sulfonate.

The L_(c) diene which may be present can, for example, be norbornadieneor, preferably, 1,5-cyclooctadiene.

Examples of bidentate chiral phosphine ligands L_(p) are:

2,4-bis(diphenylphosphino)pentane (BDPP), 2- phenyl-(3-sulfophenyl)phosphino!-4-(diphenylphosphino)pentane (BDPP-S),

2,3-bis(diphenylphosphino)butane (chiraphos),4,5-bis(diphenylphosphino-methyl)-2,2-dimethyl-1,3-dioxolane (DIOP),

2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP),1-tert-butoxycarbonyl-4-diphenylphosphino-2-(diphenylphosphinomethyl)pyrrolidine(BPPM),

2,3-bis(diphenylphosphino)bicyclo 2.2.1!hept-5-ene (norphos),

1,2-bis-(2,5-dimethylphospholano)benzene (Me-DUPHOS),1-benzyl-3,4-bis(diphenylphosphino)pyrrolidine (deguphos)

or

bis(dimethylphosphino)cyclohexane (BDPPMC).

Depending on which of the two enantiomers of the bidentate chiralphosphine ligand is used, the R-- or S-- form of I can be prepared in atargeted manner.

The cationic complexes (III) can be prepared, for example, by reacting acomplex of the general formula Ir₂ (L_(c))₂ Cl₂ !, where L_(c) is aC₄₋₁₂ -diene, with the desired bidentate chiral phosphine ligand andsubsequently with a soluble silver salt which contains the desired A⁻anion. The chloride bonded coordinately in Ir₂ (L_(c))₂ Cl₂ ! isprecipitated out as insoluble silver chloride.

The phosphine ligand L_(p) used is preferably a ferrocenylphosphine ofthe general formula ##STR4## Q is nitrogen or phosphorus, and R¹ is a C₁-C₄ -alkyl group. R² to R⁵ are in each case independently of one anotherC₁ -C₆ -alkyl, C₃ -C₇ -cycloalkyl or phenyl, which may have one or moresubstituents such as, for example, methyl, trifluoromethyl or methoxy.

Particular preference is given to phosphine ligands IV in which R¹ ismethyl.

Particular preference is also given to phosphine ligands IV in which Qis phosphorus.

Particular preference is likewise given to phosphine ligands IV in whichR² and R³ are identical and are in each case a phenyl group or asubstituted phenyl group.

Particular preference is further given to phosphine ligands IV in whichR⁴ and R⁵ are identical and are C₁ -C₄ -alkyl, cyclohexyl or optionallysubstituted phenyl.

Examples of ferrocenylphosphines of the formula IV include:

(R)-1- (S)-2-(diphenylphosphino) ferrocenyl!ethyl-di-tert-butylphosphine(Q=P, R¹ =CH₃, R² =R³ =C₆ H₅, R⁴ =R⁵ =t-Bu) (R, S)-PPF-PtBu₂ !,

(R)-1- (S)-2-(diphenylphosphino)ferrocenyl!ethyl-dicyclohexylphosphine(Q=P, R¹ =CH₃, R² =R³ =C₆ H₅, R⁴ =R⁵ =cyclohexyl) (R,S)-PPF-PCy₂ !,

(R)-1- (S)-2-(diphenylphosphino)ferrocenyl!ethyl-diphenylphosphine (Q=P,R¹ =CH₃, R² =R³ =R⁴ =R⁵ =C₆ H₅) (R,S)-PPF-PPh₂,

(R)-1-{ (S)-2- bis (4-methoxyphenyl)phosphino!ferro-cenyl}ethyl-di-tert-butylphosphine (Q=P, R¹ =CH₃, R² =R³ =p-CH₃OC₆ H₄, R⁴ =R⁵ =t-Bu) (R,S)-MeOPPF-PtBu₂ !,

(R)-1-{(S)-2-bis(4-trifluoromethylphenyl)phosphino!-ferrocenyl}ethyl-di-tert-butylphosphine(Q=P, R¹ =CH₃,

R² =R³ =p-CF₃ C₆ H₄, R⁴ =R⁵ =t-Bu) (R,S)-CF₃ PPF-PtBu₂ !,

(R)-1-(S)-2-(di-p-tolylphosphino)ferrocenyl!ethyl-di-tert-butylphosphine (Q=P,R¹ =CH₃, R² =R³ =p-CH₃ C₆ H₄, R⁴ =R⁵ =t-Bu) ((R,S)-MePPF-PtBu₂ !,

(R)-1- (S)-2-(diphenylphosphino) ferrocenyl! ethyl-bis(4-methoxy-3,5-dimethylphenyl)phosphine (Q=P, R¹ =CH₃, R² =R³ =C₆ H₅, R⁴=R⁵ =4-methoxy-3,5-dimethylphenyl) (R,S) -PPF-PMOD₂ !,

N,N-dimethyl-{ (R)-1- (S)-2-(diphenylphosphino) ferrocenyl!ethylamine}(Q=N, R¹ =R⁴ =R⁵ =CH₃, R² =R³ =C₆ H₅) (R,S)-PPFA!, and their antipodes.

Some of these ferrocenylphosphines are known from EP-A 0 564 406, EP-A 0612 758 and T. Hayashi et al., Bull. Chem. Soc. Jpn. 1980, 53,1138-1151, and some can be obtained in a similar manner to the compoundsdescribed there.

Particularly good results were achieved with (R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)-phosphino!ferrocenyl}ethyl-di-tert-butylphosphine(Q=P, R¹ =CH₃, R² =R³ =4-methoxy-3,5-dimethylphenyl, R⁴ =R⁵ =t-Bu)(R,S)-MODPF-PtBu₂ ! as phosphine ligand IV. This diphosphine and itsantipode are novel and are also provided by the present invention. Theycan be prepared by reacting the corresponding enantiomer of the knownN-N-dimethyl-1-ferrocenylethylamine with n-butyllithium andbis(4-methoxy-3,5-dimethylphenyl)chlorophosphine to give thecorresponding N,N-dimethyl-1-{2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethylamines andsubsequently replacing the dimethylamino group withdi-tert-butylphosphine.

The N,N-dimethyl-1-{2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethylamines arelike-wise novel compounds and provided by the present invention.

Of the iridium-phosphine complexes which can be obtained from(R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethyl-di-tert-butylphosphineand its antipode, preference is given to those which can be obtained byreaction with a complex of the general formula Ir₂ (L_(c))₂ Cl₂ !, whereL_(c) is a C₄₋₁₂ -diene, preferably 1,5-cyclooctadiene or norbornadiene,and subsequently with a silver salt from the group consisting of silvertetrafluoroborate, hexafluorophosphate, hexafluoroantimonate,perchlorate, acetate, trifluoroacetate, trifluoromethanesulfonate ortoluene-4-sulfonate.

Particular preference is given to those iridium-phosphine complexes inwhich L_(c) is 1,5-cyclooctadiene and the silver salt is silvertetrafluoroborate.

The asymmetric hydrogenation is advantageously carried out at atemperature of from -20° C. to 100° C., preferably from 10° C. to 40°C., and at a pressure of from 1 bar to 200 bar, preferably from 10 to100 bar.

Examples of suitable solvents are aromatic hydrocarbons, such as benzeneor toluene, ethers, such as diethyl ether, tetrahydrofuran or dioxane,chlorinated hydrocarbons, such as dichloromethane or dichloroethane,alcohols, such as methanol, ethanol or isopropyl alcohol, esters, suchas ethyl acetate or butyl acetate and mixtures of these solvents withone another or with water. Preference is given to using toluene as amixture with methanol or water (2 phases).

The stereoselectivity of the hydrogenation can be increased throughadditives. Examples thereof include inorganic or organic acids, such asphosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid,acetic acid or trifluoroacetic acid, amines, such as triethylamine,phosphines, such as triphenyl phosphine, or quarternary ammonium orphosphonium compounds, such as tetraethyl- or tetra-n-butylammoniumfluoride, chloride, bromide, iodide or hydroxide, the correspondingquaternary ammonium salts of succinimide, or the analogous phosphoniumsalts.

The starting material1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline is very unstableand readily disproportionates. It is therefore preferably used in theform of a salt. Particular preference is given to the acidic salt ofphosphoric acid, namely1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoliniumdihydrogenphosphate of the formula ##STR5##

This novel compound is likewise provided by the invention. It isobtainable in crystalline form, is stable on storage and easy toprepare. Because of the amphoteric character of the dihydrogen phosphateion, the compound also acts as a buffer and thus ensures that an optimumpH is maintained during hydrogenation.

The salt is advantageously prepared by cyclizing the N-2-(cyclohexen-1-yl)ethyl!-p-methoxyphenylacetamide disclosed in U.S.Pat. No. 4,496,762 by heating with phosphorus oxychloride in aBischler-Napieralski reaction, and then reacting with orthophosphoricacid in an organic solvent. Examples of suitable organic solvents inthis connection are ethanol, acetone, toluene or mixtures of thesesolvents, optionally with the addition of a little water.Crystallization of the salt can be significantly improved by seeding. Itis also important to carry out salt formation as soon as possible aftercyclization in order to avoid decomposition of the free base.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate how the invention is carried out butare not intended to impose any limitation. In each case only thereaction with one of the two enantiomers of the catalyst is described.

Using the other enantiomer under the same reaction conditions can ofcourse give the product having the opposite configuration.

EXAMPLES Example 1

1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline

27.3 g (0.1 mol) of N-2-(cyclohexen-1-yl)ethyl!-p-methoxyphenylacetamide and 91.4 g (0.596mol) of phosphorus oxychloride in 230 ml of toluene were heated to 100°C. under argon for 30 min. The mixture was then evaporated in a rotaryevaporator, and the residue (46 g) was washed twice with 70 ml ofpetroleum ether and then dissolved in 270 ml of dichloromethane. Thesolution was added to 270 ml of a 12% strength aqueous ammonia solutionat 0° C. with vigorous stirring. The organic phase was washed with 90 mlof water, dried over sodium sulfate and evaporated, giving 27.0 g of aviscous yellow-brown oil, which was used immediately for thehydrogenation.

¹ H NMR (CDCl₃) δ=7.1 (d, 2H, aryl-H); 6.8 (d, 2H, aryl-H); 3.8 (s, 3H,OCH₃); 3.6 (s, 2H, CH₂ Ar); 3.5 (t, 2H, CH₂ N); 2.1-2.0 (m, 4H); 1.9 (m,2H); 1.6-1.5 (m, 4H).

Example 2

1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolinium dihydrogenphosphate

27.0 g of crude 1-(p-methoxybenzyl)-3,4,5,6,7,8-hexa-hydroisoquinoline(prepared as in Example 1) were dissolved in 100 ml of ethanol. Thesolution was seeded with crystals of1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoliniumdihydrogenphosphate and admixed with a solution of 12.68 g of 85strength orthophosphoric acid in 20 ml of ethanol with stirring andcooling. The solution was cooled to 0° C. and filtered. The precipitatewas washed with ethanol and dried.

Yield: 23.19 g (65.6%); m.p.: 128.9° C.; ¹ H NMR (CDCl₃) δ=7.25 (d, 2H,aryl-H); 7.02 (d, 2H, aryl-H); 4.02 (s, 2H, CH₂ Ar); 3.85 (s, 3H, OCH₃);3.65 (t, 2H, CH₂ N); 2.55 (t, 2H); 2.4 (m, 2H); 2.3 (m, 2H) 1.7-1.6 (m,4H); ¹³ C NMR (D₂ O, int. Standard Dioxane) δ=179.0 (s); 161.1 (s);159.7 (s); 131.8 (d); 125.7 (s); 124.6 (s); 115.4 (d); 56.3 (q); 40.4(t); 31.9 (t); 27.6 (t); 24.2 (t); 22.2 (t); 21.4 (t).

Example 3

Preparation of the catalyst (III, L_(c) =η⁴ -1,5-cyclo-octadiene, L_(p)=IV, Q=P, R¹ =CH₃, R² =R³ =C₆ H₅, R⁴ =R⁵ =t-Bu, A⁻ =BF₄ ⁻)

1 g (1.49 mmol) of di-μ-chloro-bis(η⁴ -1,5-cyclo-octadiene)diiridium(I)was dissolved in 27 ml of dichloromethane under argon. 1.65 g (3.13mmol) of (R)-1-(S)-2-(diphenylphosphino)ferrocenyl!ethyl-di-tert-butylphosphine wereadded to this solution. The pale red solution was admixed with 0.592 g(2.98 mmol) of silver tetrafluoroborate in 9 ml of acetone. The reactionmixture was stirred for 1 hour at room temperature, the precipitatedsilver chloride was filtered off and the filtrate was evaporated underreduced pressure. The red-brown residue was washed and dried underreduced pressure.

Yield: 2.74 g (99%); ¹ H NMR (CDCl₃) δ=8.25 (dd, 2H); 7.75 (m, 3H);7.5-7.4 (m, 5H); 5.5 (br. m, 1H); 5.4 (br. m, 1H); 4.7 (m, 1H); 4.5 (m,1H); 4.3 (m, 1H); 3.9 (br. m, 1H); 3.7 (s, 5H); 3.4 (br. m, 1H); 3.15(br. m, 1H); 2.2 (dd, 3H); 2.2-2.0 (br. m, 2H); 1.7 (d, 9H); 1.3 (d,9H); 1.9-1.2 (br. m, 6H); ³¹ P NMR (CDCl₃, 160 MHz) δ=61.95 (d, PtBu₂);-9.97 (d, PPh₂).

Example 4

(S)-(-)-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline

An autoclave was charged with 35.4 g (0.1 mol) of1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolinium dihydrogenphosphate (prepared as in Example 2) and 62.0 mg (66.6 μmol,corresponding to a starting material/catalyst ratio=1500) of catalyst(from Example 3) and also 38.2 mg (133.4 μmol) of tetrabutylammoniumchloride After the air had been carefully removed from the closedautoclave and replaced by argon, 120 ml of oxygen-free toluene and alikewise oxygen-free solution of 4.4 g (0.11 mol) of sodium hydroxide in40 ml of water were added. Hydrogen was injected until a pressure of 70bar was reached, and the mixture was stirred at room temperature for 20h. The aqueous phase was adjusted to pH>9 by adding sodium hydroxideand, following phase separation, was extracted using a further 100 ml oftoluene. The combined organic phases were dried over sodium sulfate andevaporated under reduced pressure. The product was obtained as ayellow-brown viscous oil.

Yield: 23.5 g (91.7%); α!_(D) ²⁵ =-118 (c=1, MeOH);

The optical purity was determined by HPLC on Chiracel® OD (Daicel).

ee=80% ¹ H NMR (CDCl₃) δ=7.15 (d, 2H, aryl-H); 6.8 (d, 2H, aryl-H); 3.8(s, 3H, OCH₃); 3.25 (br. d, 1H); 3.1-2.9 (m, 2H); 2.75 (m, 1H); 2.45(dd, 1H); 2.2-2.1 (m, 1H); 2.0-1.5 (m, 9H).

Example 5

(S)-(-)-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline(catalyst preparation in situ)

Solutions of 1.28 g (5 mmol) of1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline in 10 ml ofoxygen-free toluene and of 8.4 mg (12.5 μmol) of di-μ-chloro-bis-(η⁴-1,5-cyclooctadiene)diiridium(I) and 14.9 mg (27.5 μmol) of (R)-1-(S)-2-(diphenylphosphino)-ferrocenyl!ethyl-di-tert-butylphosphine in 9ml of oxygen-free toluene and 1 ml of oxygen-free methanol wereprepared. Both solutions were introduced via cannulae into a 50ml-autoclave from which air had been carefully removed. Hydrogen wasthen injected until a pressure of 70 bar was reached. The reactionmixture was stirred at room temperature for 21 h and then evaporatedunder reduced pressure.

Yield: 1.21 g α!_(D) ²⁵ =-102 (c=1, MeOH); ee=82.5% (HPLC);

Example 6

N,N-Dimethyl-(R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethylamine

Bis(4-methoxy-3,5-dimethylphenyl)chlorophosphine was prepared byreacting bis(3,5-dimethyl-4-methoxyphenyl)phosphinous acid (T. Morimotoet al., Tetrahedron Lett. 1989, 30, 735) with phosphorus trichloride anddistilling the reaction product at 185° C./0.2 mbar. 1.71 g (5.82 mmol)of (R)-N,N-dimethyl-1-ferrocenylethylamine were dissolved in 11 ml oftert-butyl methyl ether under argon. 3.5 ml (8.75 mmol) ofn-butyllithium (2.5M solution in hexane) were added dropwise, and then asolution of 2.94 g (8.73 mmol) of bis(4-methoxy-3,5-dimethylphenyl)chlorophosphine in 5 ml of tert-butyl methyl ether was added. The brownreaction mixture was heated to 50° C. and stirred for a further 4 h.After the mixture had cooled to 0° C., 0.35 g of NaHCO₃ in 7 ml of waterwas slowly added. 10 ml of dichloromethane were added and then thereaction mixture was filtered and the insoluble residue was washed witha further 10 ml of dichloromethane. The aqueous phase was extractedthree times with 5 ml of dichloromethane and the combined organic phaseswere washed with 5 ml of water, dried over sodium sulfate andevaporated. The brown oily crude product (4.3 g) was recrystallized from14 ml of ethanol.

Yield: 0.98 g (30.2%) of a brown solid α!_(D) ²⁵ =-272.4 (c=0.4; CHCl₃);¹ H NMR (CDCl₃, 400 MHz) δ=1.28 (d, 3H, CH(NMe₂)CH₃); 1.8 (s, 6H, NMe₂),2.18 (s, 6H, PhCH₃); 2.32 (s, 6H, PhCH₃); 3.62 (s, 3H, OCH₃); 3.72 (s,3H, OCH₃); 3.85 (S, 1H, C₅ H₃); 3.92 (s, 5H, C₅ H₅); 4.06 (q, 1H,CHNMe₂); 4.22 (s, 1H, C₅ H₃); 4.35 (s, 1H, C₅ H₃); 6.82 (d, 2H₁, C₆ H₂);7.25 (d, 2H, C₆ H₂); ³¹ P NMR (CDCl₃, 160 MHz) δ=-23.7

Example 7

(R)-1-{(S)-2- bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethyl-di-tert-butylphosphine0.979 g (1.76 mmol) of N,N-dimethyl-(R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethylamine(prepared as in Example 6) was suspended in 18 ml of acetic acid underargon. 0.345 g (2.36 mmol) of di-tert-butylphosphine was then added andthe reaction mixture was stirred at 80° C. for 2.5 h. The reactionsolution was evaporated under reduced pressure, giving 1.3 g of ared-brown oil which was chromatographed over a silica gel column usingethyl acetate/hexane/ethanol (47.5: 47.5:5).

Yield: 0.9 g (77%) of an orange-red solid α!_(D) ²⁵ =-324.6 (c=0.4;CHCl₃); ¹ H NMR (CDCl₃, 400 MHz) δ=0.97 (d, 9H; tBu) 1.15 (d, 9H; tBu);1.82 (dd, 3H, CHPtBu₂ CH₃); 2.18 (s, 6H, PhCH₃); 2.25 (s, 6H, PhCH₃);3.35 (q, 1H, CHPtBu₂); 3.62 (s, 3H, OCH₃); 3.72 (s, 3H, OCH₃); 3.88 (s,5H, C₅ H₅); 3.95 (s, 1H, C₅ H₃); 4.2 (s, 1H, C₅ H₃); 4.35 (s, 1H, C₅H₃); 6.82 (d, 2H, C₆ H₂); 7.3 (d, 2H, C₆ H₂); ³¹ P NMR (CDCl₃, 160 MHz)δ=49.3 (d, ⁴ J_(pp) =44.5 Hz, PtBu₂); -26.7 (d, ⁴ J_(pp) =44.5 Hz,PPh₂).

Example 8

Preparation of the catalyst:

115 mg (170.8 μmol) of di-μ-chloro-bis(η⁴-1,5-cyclooctadiene)diiridium(I) were dissolved in 3.4 ml ofdichloromethane under argon. 250 mg (379.6 μmol) of (R)-1-{(S)-2-bis(3,5-dimethyl-4-methoxyphenyl)-phosphino!-ferrocenyl}ethyl-di-tert-butylphosphine(prepared as in Example 7) were added to this solution at 0° C. The palered solution was admixed with 67.9 mg (341.6 μmol) of silvertetrafluoroborate in 1.1 ml of acetone. The reaction mixture was stirredat 0° C. for 1 h, the precipitated silver chloride was filtered off andthe filtrate was evaporated under reduced pressure. The red-brownresidue was washed with diethyl ether and dried under reduced pressure.

Yield: 350 mg (98%) ¹ H NMR (CDCl₃, 400 MHz) δ=7.95 (d, 2H); 7.05 (d,2H); 5.6 (br. s, 1H); 5.25 (br. s, 1H); 4.7 (s, 1H); 4.5 (s, 1H); 4.3(s, 1H); 3.84 (s, 3H); 3.82 (s, 3H); 3.78 (s, 5H); 3.7 (br. s, 1H); 3.3(br. s, 2H); 2.45 (s, 6H); 2.3 (s, 6H); 2.2 (dd, 3H); 2.3-2.1 (br. m,2H); 1.65 (d, 9H); 1.25 (d, 9H); 2.0-1.5 (br. m, 6H); ³¹ P NMR (CDCl₃,160 MHz) δ=61.5 (d, PtBu); -7.45 (d, PPh₂)

Example 9

(S)-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline

An autoclave was charged with 3.54 g (10 mmol) of1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoliniumdihydrogenphosphate (prepared as in Example 2) and 6.97 mg (6.66 μmol,corresponding to a starting material/catalyst ratio=1500) of catalystfrom Example 8 and also 8.68 mg of tetrabutylammonium bromide. After theair had been carefully removed from the closed autoclave and replaced byargon, 14 ml of oxygen-free toluene and a likewise oxygen-free solutionof 440 mg of sodium hydroxide in 40 ml of water were added. Hydrogen wasinjected until a pressure of 70 bar was reached, and the mixture wasstirred at room temperature for 22 h. The aqueous phase was adjusted topH>9 by adding sodium hydroxide and, following phase separation, wasextracted with a further 10 ml of toluene. The combined organic phaseswere dried over sodium sulfate and evaporated under reduced pressure.The product was obtained as a yellow-brown oil.

Yield: 2.32 g (90.2%) α!_(D) ²⁵ =-131.7 (c=1, MeOH); The optical puritywas determined by HPLC on Chiracel® OD (Daicel). ee=89.2%.

Examples 10-24

The reactions summarized in Table 1 below were carried out as describedunder Examples 4 and 5. The "Starting material" column gives the formulanumbers of the starting materials used. The "P" column gives theprecursor complex used. "A" represents Ir(cod)L_(p) (prepared as inExample 3) (cod=1,5-cyclooctadiene) and "B" represents Ir₂ (cod)₂ Cl₂ !.The abbreviations listed in the "Ligand" column correspond to theabbreviations given in brackets in the above list of ligands. The "SM/C"column gives the molar ratio of starting material: catalyst. "RT" isroom temperature. The abbreviations used in the "Additives" column arein detail:

TBACL=tetra-n-butylammonium chloride

TBAF=tetra-n-butylammonium fluoride

TBAI=tetra-n-butylammonium iodide

TBASI=tetra-n-butylammonium, salt with succinimide

TBPBr=tetra-n-butylphosphonium bromide

TEAH=tetraethylammonium hydroxide

                                      TABLE 1    __________________________________________________________________________    Starting                    p           ee    material          P Ligand                  SM/C                     Solvent                            Temp.                                 bar!                                   Additives                                             % !    __________________________________________________________________________    30 mmol V          A (R,S)-PPF-                  600                     80 ml  RT  70 2.0 mmol 85.4            PtBu.sub.2                     dioxane/6.3 ml                                   TBACl, 24 mmol                                            (S)                     H.sub.2 O     NaOH, 24 mmol                                   TEAH    30 mmol V          A (R,S)-PPF-                  1000                     38 ml  RT  10 0.12 mmol                                            79.1            PtBu.sub.2                     toluene/10 ml TBACl, 33 mmol                                            (S)                     H.sub.2 O     NaOH    20 mmol II          A (R,S)-PPF-                  800                     19 ml  RT  70 6.66 mmol H.sub.3 PO.sub.4                                            71.1            PtBu.sub.2                     toluene/1 ml           (S)                     MeOH    5 mmol II          B (R,S)-PPF-                  200                     19 ml  RT  70          85.2            PtBu.sub.2                     toluene/1 ml           (S)                     MeOH    10 mmol V          A (R,S)-PPF-                  3000                     14 ml  RT  70 11 mmol NaOH,                                            35.8            PtBu.sub.2                     toluene/3.3 ml                                   13.3 mmol TBAI                                            (S)                     H.sub.2 O    10 mmol V          A (R,S)-                  1500                     7 ml toluene/7                            RT  70 11 mmol NaOH,                                            75.8            MODPF-   ml dioxane/3.3                                   13.3 mmol TBAI                                            (S)            PtBu.sub.2                     ml H.sub.2 O    5 mmol II          B (+)-  100                     10 ml  RT  70          30.7            Norphos  toluene/10 ml          (S)                     MeOH    5 mmol II          B (R,R)-                  100                     2 ml   RT  70          38.4            Chiraphos                     toluene/18 ml          (R)                     MeOH    5 mmol II          B (R,S)-PPF-                  100                     20 ml MeOH                            RT  70          53.9            Pcy.sub.2                       (R)    5 mmol II          B (R,R)-                  100                     20 ml MeOH                            0° C.                                70          16.7            BDPP-S                          (S)    5 mmol II          B (+) - (S,S)                  100                     20 ml MeOH                            RT  70          18.9            BDPPMC                          (S)    5 mmol II          B (+) - (S,S)                  100                     20 ml toluene                            RT  70          16.7            BDPPMC                          (R)    10 mmol V          A (R,S)-PPF-                  1000                     14 ml toluene,                            RT  70 11 mmol NaOH,                                            79.7            PtBu.sub.2                     3.3 ml H.sub.2 O                                   40 μmol TBPBr                                            (S)    10 mmol V          A (R,S)-PPF-                  1000                     14 ml toluene,                            RT  70 11 mmol NaOH,                                            82.5            PtBu.sub.2                     3.3 ml H.sub.2 O                                   40 μmol TBAF                                            (S)    10 mmol V          A (R,S)-PPF-                  1000                     14 ml toluene,                            RT  70 11 mmol NaOH,                                            79.6            PtBu.sub.2                     3.3 ml H.sub.2 O                                   40 μmol TBASI                                            (S)    __________________________________________________________________________

I claim:
 1. Process for the preparation of optically active1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline of the formula##STR6## wherein 1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolineof the formula ##STR7## or a salt thereof is asymmetrically hydrogenatedin the presence of a catalytically effective optically activeiridium-phosphine complex.
 2. Process according to claim 1, wherein thecatalytically effective optically active iridium-phosphine complex isformed from a complex of the formula

     IrL.sub.c L.sub.p !+A.sup.-                               III

or from the reaction product of Ir(L_(c))₂ Cl₂ ! or Ir(L_(c))₂ !+BF₄ ⁻and L_(p), where in each case L_(c) is C₄₋₁₂ -diene, L_(p) is a chiralbidentate phosphine and A⁻ is an anion.
 3. Process according to claim 2,wherein L_(p) is 1,5-cyclooctadiene.
 4. Process according to claim 2,wherein L_(p) is a ferrocenylphosphine of the formula ##STR8## where Qis nitrogen or phosphorus, R¹ is a C₁₋₄ -alkyl group, and R² to R⁵ areindependently of one another C₁₋₆ -alkyl, C₃₋₇ -cycloalkyl or optionallysubstituted phenyl.
 5. Process according to claim 4, wherein R¹ ismethyl.
 6. Process according to claim 5, wherein Q is phosphorus. 7.Process according to claim 6, wherein R² and R³ are identical and arephenyl or substituted phenyl.
 8. Process according to claim 7, whereinR² and R³ are 4-methoxy-3,5-dimethylphenyl.
 9. Process according toclaim 8, wherein R⁴ and R⁵ are identical and are C₁₋₄ -alkyl, cyclohexylor optionally substituted phenyl.
 10. Process according to claim 9,wherein the L_(p) ligand is (R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethyl-di-tert-butyl-phosphineor its antipode.
 11. Process according to claim 10, wherein that1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline is used in theform of the dihydrogenphosphate of the formula: ##STR9##
 12. Processaccording to claim 10, wherein1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline is used in theform of the dihydrogenphosphate of the formula: ##STR10##
 13. Processfor the preparation of1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoliniumdihydrogenphosphate, wherein N-2-(cyclohexen-1-yl)ethyl!-p-methoxyphenylacetamide is cyclized byheating with phosphorus oxychloride and then reacted withorthophosphoric acid in an organic solvent.
 14. (R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)-phosphino!ferrocenyl)ethyl-di-tert-butylphosphine.15. (S)-1-{(R)-2-bis(4-methoxy-3,5-dimethylphenyl)-phosphino!ferrocenyl}ethyl-di-tert-butylphosphine.16. Process according to claim 4, wherein Q is phosphorus.
 17. Processaccording to claim 4, wherein R² and R³ are identical and are phenyl orsubstituted phenyl.
 18. Process according to claim 4, wherein R⁴ and R⁵are identical and are C₁₋₄ -alkyl, cyclohexyl or optionally substitutedphenyl.
 19. Process according to claim 4, wherein the L_(p) ligand is(R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethyl-di-tert-butyl-phosphineor its antipode.
 20. Process according to claim 1, wherein1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline is used in theform of the dihydrogenphosphate of the formula: ##STR11##
 21. Processaccording to claim 1 for the preparation of an iridium-phosphine complexcomprising reacting a complex of the formula Ir₂ (L_(c))₂ Cl₂ !, whereL_(c) is a C₄₋₁₂ -diene with the (R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethyl-di-tert-butylphosphineand a silver salt from the group consisting of silver tetraflurorborate,hexafluorophosphate, hexaflucroantimonate, perchlorate, acetate,trifluoroacetate, trifluoromethanesulfonate or toluene-4-sulfonate. 22.Process according to claim 21 wherein L_(c) is 1,5-cyclooctadiene ornorbornadiene.
 23. Process according to claim 1 wherein theiridium-phosphine complex which has been prepared by reacting a complexof the formula Ir₂ (L_(c))₂ Cl₂ !, where L_(c) is a C₄₋₁₂ -diene withthe (R)-1-{(S)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethyl-di-tert-butylphosphineand a silver salt from the group consisting of silver tetraflurorborate,hexafluorophosphate, hexafluoroantimonate, perchlorate, acetate,trifluoroacetate, trifluoromethanesulfonate or toluene-4-sulfonate. 24.Process according to claim 1 for the preparation of an iridium-phosphinecomplex comprising reacting a complex of the formula Ir₂ (L_(c))₂ Cl₂ !,where L_(c) is a C₄₋₁₂ -diene with the (S)-1-{(R)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethyl-di-tert-butylphosphineand a silver salt from the group consisting of silver tetraflurorborate,hexafluorophosphate, hexafluoroantimonate, perchlorate, acetate,trifluoroacetate, trifluoromethanesulfonate or toluene-4-sulfonate. 25.Process according to claim 24 wherein L_(c) is 1,5-cyclooctadiene ornorbornadiene.
 26. Process according to claim 1 wherein theiridium-phosphine complex which has been prepared by reacting a complexof the formula Ir₂ (L_(c))₂ Cl₂ !, where L_(c) is a C₄₋₁₄ -diene withthe (S)-1-{(R)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}ethyl-di-tert-butylphosphineand a silver salt from the group consisting of silver tetraflurorborate,hexafluorophosphate, hexafluoroantimonate, perchlorate, acetate,trifluoroacetate, trifluoromethanesulfonate or toluene-4-sulfonate. 27.Iridium-phosphine complex according to claim 23, wherein L_(c) is1,5-cyclooctadiene and the silver salt is silver tetrafluoroborate. 28.Process according to claim 26, wherein L_(c) is 1,5-cyclooctadiene ornorbornadiene.
 29. N-N-Dimethyl-(S)-1-{(R)-2-bis(4-methoxy-3,5-dimethylphenyl)phosphino!ferrocenyl}-ethylamine.